The Branch has a long-standing involvement in the systematic evaluation of chemotherapeutic drugs alone or in combination with radiotherapy. As more individuals become long-term cancer survivors, there is greater need to evaluate risk-benefit ratios for various treatment protocols. Second malignant neoplasms constitute the most common cause of mortality in patients cured of Hodgkin's disease (HD), with lung cancer representing the most frequent solid tumor. Despite the frequency of this cancer, analytic data which describe the importance of chemotherapy and radiotherapy in its development have been conflicting, sparse and inadequately controlled for smoking. REB conducted a nested case-control study of lung cancer within a cohort of 19,046 one-year survivors of HD focused on radiation effects. The study population consisted of 227 patients with lung cancer and 455 matched controls. Unique features included dose determinations to the specific location in the lung where each cancer developed and quantitative data on both chemotherapy and tobacco use obtained from medical records. The estimated excess relative risk (ERR) per Gy was 0.15 (95% CI: 0.06-0.39), and there was little evidence of departure from linearity even though lung doses for the majority of Hodgkin's disease patients treated with radiotherapy exceeded 30 Gy. The interaction of radiation and chemotherapy that included alkylating agents was almost exactly additive, and a multiplicative relationship could be rejected (P=0.017). Conversely, the interaction of radiation and smoking was consistent with a multiplicative relationship, but not with an additive relationship (P<0.001). The ERR/Gy for males was about four times that for females, although the difference was not statistically significant. There was little evidence of modification of the ERR/Gy by time since exposure (after a 5-year minimum latent period), age at exposure, or attained age. To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD, a case-control study of breast cancer was conducted within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger. Breast Cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P=.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P=.003 for trend). Risk also was low (RR 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses. The high radiation related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness. A recently initiated, multi-center international study will provide new information on the relation between radiation dose and cancer risk for three gastrointestinal (GI) organs (stomach, esophagus, and pancreas) for which few quantitative data exist. The study will also supply important new information relevant to clinical decision-making, as it will be undertaken in cancer survivors, and constitutes the first analytic investigation of second GI tumors, incorporating information on radiation dose and chemotherapy. These case-control studies of GI tumors will be set within international cohorts of patients with testicular cancer, Hodgkin disease, breast cancer and cervical cancer. In addition, available biologic samples will be collected to conduct a preliminary study of single nucleotide polymorphisms in DNA repair genes. Cancer Risks following Bone Marrow Transplantation A case-control study conducted within a cohort of 29,000 recipients of an allogeneic bone marrow transplant found that long-duration of immunosuppressive drug therapy given to treat chronic graft-versus-host disease is strongly associated with increased risk of secondary squamous cell solid cancers, particularly those of the buccal cavity and skin. Risks were highest for patients treated for more than 24 months and those receiving multiple drug regimens including azathioprine. A cohort of 1,600 Retinoblastoma (RB) patients continues to be monitored for cancer risk, and RB patients who have developed melanoma are undergoing clinical examination for dysplastic nevi syndrome, lipomas, and mutations in melanoma susceptibility genes. DNA collected from hereditary RB patients with a second cancer are being genotyped for mutations in their RB1 gene to identify mutations that increase susceptibility to a second cancer. In collaboration with the Genetic Epidemiology Branch and cancer registries in four Nordic countries, we found that overall cancer incidence was not greater than expected in family members of ataxia-telangiectasia patients. Breast cancer risk was reported to be increased in mothers, but not other female relatives. Expansion of the original cohort, sequencing of the ATM gene in patients and family members, and genotype-phenotype analyses are also in progress. A multi-center retrospective cohort study of 5,573 women with scoliosis found them 70% more likely to die from breast cancer than women in the general population. A statistically significant linear dose-response relationship was observed, with an excess relative risk per Gy of 5.4. A recently completed analysis of breast cancer incidence through 1993 revealed an excess relative risk of 3.3 per Gy after adjustment for established breast cancer risk factors. Subjects with exposures of 20 or more cGy had a more than 2-fold risk compared to those with exposures <10 cGy. The dose-response was stronger for subjects who reported a family history of breast cancer than for those without affected female relatives. Based on small numbers of cases in some strata and a relatively narrow age range during which most of the exposure was received, no significant differences were observed in sensitivity to radiation carcinogenesis according to age at exposure or stage of exposure as defined by windows of reproductive events (i.e., before breast budding, between breast budding and menarche, and between menarche and 1st birth, which represent different stages of breast tissue differentiation and proliferation). During FY05, we propose to extend the follow-up for cancer incidence through 2003, with a main focus on incident breast cancer and possible genetic influences on the risk of radiation-induced breast cancer in this population.